Murine hybridoma cell line 9.3 has been deposited with the American Type Culture Collection in Rockville, Md., in compliance with the provisions of the Budapest Treaty, and has been assigned ATCC Designation No. HB10271.
The present invention generally relates to immunotherapy. More particularly, the present invention relates to immunotherapy involving regulation of the CD28 T cell surface molecule.
Thymus derived lymphocytes, referred to as T cells, are important regulators of in vivo immune responses. T cells are involved in cytotoxicity and delayed type hypersensitivity (DTH), and provide helper functions for B lymphocyte antibody production. In addition, T cells produce a variety of lymphokines which function as immunomodulatory molecules, such as for example, interleukin-2 (IL-2), which can facilitate the cell cycle progression of T cells; tumor necrosis factor-xcex1 (TNF-xcex1) and lymphotoxin (LT), cytokines shown to be involved in the lysis of tumor cells; interferon-xcex3 (IFN-xcex3), which displays a wide variety of anti-viral and anti-tumor effects; and IL-3 and granulocyte-macrophage colony stimulating factor (GM-CSF), which function as multilineage hematopoietic factors.
Current immunotherapeutic treatments for diseases such as cancer, acquired immunodeficiency syndrome (AIDS) and attending infections, involve the systemic administration of lymphokines, such as IL-2 and IFN-xcex3, in an attempt to enhance the immune response. However, such treatment results in non-specific augmentation of the T cell-mediated immune response, since the lymphokines administered are not specifically directed against activated T cells proximate to the site of infection or the tumor. In addition, systemic infusions of these molecules in pharmacologic doses leads to significant toxicity. Present therapies for immunodeficient or immunodepressed patients also involve non-specific augmentation of the immune system using concentrated xcex3-globulin preparations. The stimulation of the in vivo secretion of immunomodulatory factors has not, until now, been considered a feasible alternative due to the failure to appreciate the effects and/or mechanism and attending benefits of such therapy.
It would thus be desirable to provide a method of immunotherapy which enhances the T cell-mediated immune response and which is directed specifically toward T cells activated by an antigen produced by the targeted cell. It would further be desirable to provide a method of immunotherapy which could take advantage of the patient""s natural immunospecificity. It would also be desirable to provide a method of immunotherapy which can be used in immunodepressed patients. It would additionally be desirable to provide a method of immunotherapy which does not primarily rely on the administration of immunomodulatory molecules in amounts having significant toxic effects.
It would also be desirable to provide a method of immunotherapy which, if so desired, could be administered directly without removal and reintroduction of T cell populations. It would further be desirable to provide a method of immunotherapy which could be used not only to enhance, but to suppress T cell-mediated immunoresponses where such immunosuppression would be advantageous, for example, in transplant patients, in patients exhibiting shock syndrome and in certain forms of autoimmune disease.
The present invention comprises a method of immunotherapy in which the T cell-mediated immune response is regulated by the CD28 pathway. Binding of the CD28 receptor with anti-CD28 antibodies or other stimulatory binding equivalents induces activated T cell-mediated lymphokine production. Immunosuppression or down-regulation is achieved by preventing CD28 receptor binding to stimulatory ligands or inactivation of the CD28 signal transduction pathway.
The method of immunotherapy of the present invention takes advantage of the surprising and heretofore unappreciated effects of stimulation of the CD28 surface receptor molecule of activated T cells. By activated T cells is meant cells in which the immune response has been initiated or xe2x80x9cactivated,xe2x80x9d generally but not necessarily by the interaction of the T cell receptor (TCR)/CD3 T cell surface complex with a foreign antigen or its equivalent. While such activation results in T cell proliferation, it results in only limited induction of T cell effector functions such as lymphokine production.
Stimulation of the CD28 cell surface molecule with anti-CD28 antibody results in a marked increase of T cell lymphokine production. Surprisingly, even when the stimulation of the TCR/CD3 complex is maximized, upon costimulation with anti-CD28, there is a substantial increase in the levels of IL-2 lymphokine, although there is no significant increase in T cell proliferation over that induced by anti-TCR/CD3 alone. Even more surprisingly, not only are IL-2 levels significantly increased, but the levels of an entire set of lymphokines, hereinafter referred to as THCD28 lymphokines, previously not associated with CD28 stimulation are increased. Remarkably both the T cell proliferation and increased lymphokine production attributable to CD28 stimulation also exhibit resistance to immunosuppression by cyclosporine and glucocorticoids.
The method of immunotherapy of the present invention thus provides a method by which the T cell-mediated immune response can be regulated by stimulating the CD28 T cell surface molecule to aid the body in ridding itself of infection or cancer. The method of the present invention can also be used not only to increase T cell proliferation, if so desired, but to augment or boost the immune response by increasing the levels and production of an entire set of T cell lymphokines now known to be regulated by CD28 stimulation.
Moreover, because the effectiveness of CD28 stimulation in enhancing the T cell immune response appears to require T cell activation or some form of stimulation of the TCR/CD3 complex, the method of immunotherapy of the present invention can be used to selectively stimulate T cells preactivated by disease or treatment to protect the body against a particular infection or cancer, thereby avoiding the non-specific toxicities of the methods presently used to augment immune function. In addition, the method of immunotherapy of the present invention enhances T cell-mediated immune functions even under immunosuppressed conditions, thus being of particular benefit to individuals suffering from immunodeficiencies such as AIDS.
It will also be appreciated that although the following discussion of the principles of the present invention exemplifies the present invention in terms of human therapy, the methods described herein are similarly useful in veterinary applications.
A better understanding of the present invention and its advantages will be had from a reading of the detailed description of the preferred embodiments taken in conjunction with the drawings and specific examples set forth below.